The present invention relates to the field of trauma intervention, and in particular, the treatment of severe burns with parenteral therapy involving administration of chemically modified hemoglobin.
The occurrence of severe burn injury sets in motion a complex series of biochemical and physiological events that critically affect the course of recovery and even the survival of the patient. In the early hypodynamic stage of burn shock, there is a marked suppression of mean arterial blood pressure (MAP), cardiac output (CO), systemic vascular resistance (SVR), oxygen delivery (DO2), and an increase in base deficit. Associated with these changes is a profound increase in capillary permeability resulting in extravasation of large amounts of plasma fluids. Most of these fluids are retained in the extravascular tissue matrix as edema.
Many of these effects are mediated by vasoactive hormones and other substances. Levels of IL-1, IL-6, vasopressin and nitric oxide are elevated, and contribute to the systemic effects. At the local inflammatory level, products of arachidonic acid metabolism such as leukotrienes and prostaglandins increase microvascular permeability. Thromboxane A2, and related metabolites, are produced locally in the burn wound and cause injury by increasing tissue ischemia. Other vasoactive mediators, such as histamine, bradykinin, and oxygen radicals generated post-burn contribute to edema either directly by affecting vascular permeability, or indirectly by causing an increase in microvascular hydrostatic pressure.
A marked decrease in the delivery of oxygen to the burn wound is a consequence of reduced CO, lower MAP, reduced cardiac contractility, and the edema which interferes with tissue perfusion because of occlusion of capillaries. Resolution of the hypodynamic state with progression to the hyperdynamic stage is imperative. Failure to achieve this transition is correlated with increased mortality. Reversal of base deficit, and stabilization of cardiac parameters during the first 36 hours post-trauma, may be correlated with enhanced survival.
By the 1970""s, the importance of restoring circulating fluid volume by administration of resuscitative fluids was well recognized. Several regimens were developed to calculate the desired resuscitative fluid volume. The use of colloid and crystalloid solutions is described in detail in Demling, et al., Burn Trauma, Thieme Medical Publishers: New York (1989). The Parkland formula requires administration of 4 mL Ringer""s Lactate/kg of body weight divided by the percent total burn surface area (TBSA) during the first 24 hours post-burn. In the Brooke formula, 2 mL Ringer""s Lactate/kg of body weight divided by TBSA is supplemented with 2000 mL of 5% dextrose during the first 24 hours post-burn trauma. A third formula utilized by the Shriners Burn Institute is composed of Lactated Ringer""s solution containing 1.25% salt-poor human albumin, administered in a quantity of 2000-500 mL in a 24 hour period.
The foregoing fluid replacement treatments, while generally beneficial in restoring circulating volume, may actually impede tissue perfusion. The continued extravasation of the large amount of infused fluid exacerbates edema and decreases oxygen delivery systemically and at the burn site. The various resuscitative formulae involving colloids improve oncotic pressure, but do not regularly result in an improvement in clinical outcome. In some instances, life threatening complications may occur which are directly attributable to treatment, as in the occurrence of pulmonary edema in the administration of oncotic solutions.
The present invention provides a method of treating burn shock, by administration of hemoglobin chemically modified to decrease its affinity for oxygen. Chemically modified hemoglobin having a P50 value of about 20-55, preferably 25-35, is administered in for example, a resuscitative fluid to provide a total cumulative quantity of 100 to 2000 mg/kg of body weight. The resuscitative solution can be, for example, Lactated Ringer""s solution.
In one embodiment, the hemoglobin chemically modified to decrease its affinity for oxygen is administered in a resuscitation fluid volume delivered in a cumulative dose of 100 to 2000 mg/kg of body weight during the course of a fluid resusucitation regimen. The resuscitation regimen can be selected from any one of the established protocols such as the Parkland formula, Evans formula, Brooke formula, or accepted variants thereof. Administration time is generally about 24 hours post-burn, but the time may be shortened or expanded depending on the fluid condition of the patient.
In some of the treatment protocols the rate of administration may vary over the course of the first 24 hours post-burn. For example, in the Parkland formula, half of the resuscitative fluid volume is administered during the first 8 hour period, and the remaining half of the fluid volume is administered during the remainder of 24 hours post-burn. A resuscitative solution containing hemoglobin may be administered according to this or other established formula.